Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.
Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.
Immunity. 2017 Nov 21;47(5):903-912.e4. doi: 10.1016/j.immuni.2017.10.007. Epub 2017 Nov 7.
Alveolar macrophages (AMs) derive from fetal liver monocytes, which colonize the lung during embryonic development and give rise to fully mature AMs perinatally. AM differentiation requires granulocyte macrophage colony-stimulating factor (GM-CSF), but whether additional factors are involved in AM regulation is not known. Here we report that AMs, in contrast to most other tissue macrophages, were also dependent on transforming growth factor-β receptor (TGF-βR) signaling. Conditional deletion of TGF-βR in mice at different time points halted the development and differentiation of AMs. In adult mice, TGF-β was also critical for AM homeostasis. The source of TGF-β was AMs themselves, indicative of an autocrine loop that promotes AM self-maintenance. Mechanistically, TGF-βR signaling resulted in upregulation of PPAR-γ, a signature transcription factor essential for the development of AMs. These findings reveal an additional layer of complexity regarding the guidance cues, which govern the genesis, maturation, and survival of AMs.
肺泡巨噬细胞（AMs）来源于胎肝单核细胞，它们在胚胎发育过程中定殖于肺部，并在围产期分化为完全成熟的 AMs。AM 分化需要粒细胞巨噬细胞集落刺激因子（GM-CSF），但尚不清楚是否有其他因素参与 AM 的调节。在这里，我们报告称，与大多数其他组织巨噬细胞不同，AMs 也依赖于转化生长因子-β 受体（TGF-βR）信号。在不同时间点对小鼠进行 TGF-βR 条件性缺失会阻止 AMs 的发育和分化。在成年小鼠中，TGF-β 对于 AM 的稳态也至关重要。TGF-β 的来源是 AMs 本身，表明存在一个自分泌环，促进 AM 自我维持。从机制上讲，TGF-βR 信号导致 PPAR-γ 的上调，PPAR-γ 是 AMs 发育所必需的特征性转录因子。这些发现揭示了关于指导线索的另一个复杂性，这些线索控制 AMs 的发生、成熟和存活。
